The occurrence of environmental antibiotic resistance genes (ARGs) are often attributed to selective pressure from antibiotics from point source pollution. However, the potential effects of natural production of antibiotics, environmental factors, and anthropogenic pressure on the development and spread of ARGs have not been fully investigated. This study evaluated the occurrence and distribution of erythromycin resistance methylase (erm) genes in urban soils. The ermA, ermB, ermC, ermD, ermF, ermG, ermT, and ermY genes were detected with detection frequencies ranging from 20% to 80% and abundances ranging between 5...

Dozens of type A malyngamides, principally identified by a decorated six-membered cyclohexanone head group and methoxylated lyngbic acid tail, have been isolated over several decades. Their environmental sources include macro- and microbiotic organisms, including sea hares, red alga, and cyanobacterial assemblages but their true producing organism has remained enigmatic. Many type A analogs display potent bioactivity in human-health related assays, spurring an interest in this molecular class and its biosynthetic pathway...

Teredinidae are a family of highly adapted wood-feeding and wood-boring bivalves, commonly known as shipworms, whose evolution is linked to the acquisition of cellulolytic gammaproteobacterial symbionts harbored in bacteriocytes within the gills. In the present work we applied metagenomics to characterize microbiomes of the gills and digestive tract of Neoteredo reynei, a mangrove-adapted shipworm species found over a large range of the Brazilian coast. Comparative metagenomics grouped the gill symbiont community of different N...

Marine natural products have become an increasingly important source of new drug leads during recent years. In an attempt to identify novel anti-microbial natural products by bioprospecting deep-sea Actinobacteria, three new angucyclines, nocardiopsistins A-C, were isolated from Nocardiopsis sp. strain HB-J378. Notably, the supplementation of the rare earth salt Lanthanum chloride (LaCl3 ) during fermentation of HB-J378 significantly increased the yield of these angucyclines. The structures of nocardiopsistins A-C were identified by 1D and 2D NMR and HR-MS data...

Microbial culture conditions in the laboratory, which conventionally involve the cultivation of one strain in one culture vessel, are vastly different from natural microbial environments. Even though perfectly mimicking natural microbial interactions is virtually impossible, the cocultivation of multiple microbial strains is a reasonable strategy to induce the production of secondary metabolites, which enables the discovery of new bioactive natural products. Our coculture of marine Streptomyces and Bacillus strains isolated together from an intertidal mudflat led to discover a new metabolite, dentigerumycin E ( 1 )...

Colibactins are genotoxic secondary metabolites produced in select Enterobacteriaceae, which induce downstream DNA double-strand breaks (DSBs) in human cell lines and are thought to promote the formation of colorectal tumors. Although key structural and functional features of colibactins have been elucidated, the full molecular mechanisms regulating these phenotypes remain unknown. Here, we demonstrate that free model colibactins induce DSBs in human cell cultures and do not require delivery by host bacteria...

Since 2016 October, the active galaxy PKS 2247-131 has undergone a γ-ray outburst, which we studied using data obtained with the Fermi Gamma-ray Space Telescope. The emission arises from a relativistic jet in PKS 2247-131, as an optical spectrum only shows a few weak absorption lines, typical of the BL Lacertae sub-class of the blazar class of active galactic nuclei. Here we report a ≃34.5 day quasi-periodic oscillation (QPO) in the emission after the initial flux peak of the outburst. Compared to one-year time-scale QPOs, previously identified in blazars in Fermi energies, PKS 2247-131 exhibits the first clear case of a relatively short, month-like oscillation...

Mechanistic understanding of microbe-host interactions is critical to developing therapeutic strategies for targeted modulation of the host immune system. Different members of the gut symbiont species Lactobacillus reuteri modulate host health by, for example, reduction of intestinal inflammation. Previously, it was shown that L. reuteri activates the aryl-hydrocarbon receptor (AhR)-a ligand-activated transcription factor that plays an important role in the mucosal immune system-by production of tryptophan catabolites...

PURPOSE: To investigate the multiple-dose pharmacokinetics (PK), pharmacodynamics (PD), and tolerability of palosuran, a selective, potent antagonist of the human UT receptor. METHODS: This was a double-blind, randomized, placebo-controlled study. Three dose levels were investigated for PKs, PDs, and safety in sequential groups of 8 subjects each. RESULTS: The plasma concentration-time profile is characterized by rapid absorption and 2 peaks after drug administration...

In the last decades, human protein kinases (PKs) have been relevant as targets in the development of novel therapies against many diseases, but the study of Mycobacterium tuberculosis PKs (MTPKs) involved in tuberculosis pathogenesis began much later and has not yet reached an advanced stage of development. To increase knowledge of these enzymes, in this work we studied the structural features of MTPKs, with focus on their ATP-binding sites and their interactions with inhibitors. PknA, PknB, and PknG are the most studied MTPKs, which were previously crystallized; ATP-competitive inhibitors have been designed against them in the last decade...

Polyketides are a unique class of molecules with attractive bioactive and chemical properties. As a result, biorenewable production is being explored with these molecules as potential pharmaceutical, fuel and material precursors. In particular, type III polyketide synthases enable access to a diverse class of chemicals using a relatively simple biochemical synthesis pathway. In this review, we highlight recent advances in the engineering of microbial hosts for the production of type III PKS-derived polyketides...

Clinical isolates of Yersinia , Klebsiella , and Escherichia coli frequently secrete the small molecule metallophore yersiniabactin (Ybt), which passivates and scavenges transition metals during human infections. YbtT is encoded within the Ybt biosynthetic operon and is critical for full Ybt production in bacteria. However, its biosynthetic function has been unclear because it is not essential for Ybt production by the in vitro reconstituted nonribosomal peptide synthetase/polyketide synthase (NRPS/PKS) pathway...

Polyketide C-methylation occurs during a programmed sequence of dozens of reactions carried out by multidomain polyketide synthases (PKSs). Fungal PKSs perform these reactions iteratively, where a domain may be exposed to and act upon multiple enzyme-tethered intermediates during biosynthesis. We surveyed a collection of C-methyltransferase (CMeT) domains from nonreducing fungal PKSs to gain insight into how different methylation patterns are installed. Our in vitro results show that control of methylation resides primarily with the CMeT, and CMeTs can intercept and methylate intermediates from noncognate nonreducing PKS domains...

We present an application of a quantitative systems pharmacology (QSP) model to support a regulatory decision, specifically in assessing the adequacy of the proposed dosing regimen. On January 23, 2015, the US Food and Drug Administration (FDA) approved Natpara (human parathyroid hormone (PTH)) to control hypocalcemia in patients with hypoparathyroidism. Clinical trial results indicated that although once-daily PTH reduced calcium and vitamin D dose requirement while maintaining the normocalcemia, the regimen was not adequate to control hypercalciuria...

OBJECTIVE: To highlight importance of detailed ultrasound examination in fetuses with known normal karyotype (and micro-array result) from CVS. In case of markedly abnormal ultrasound result repeated karyotyping by amniocentesis should be considered. Sample should be analyzed by routine cytogenetic techniques, however also micro-array and targeted FISH should be added in order to achieve most accurate diagnosis. CASE REPORT: We report prenatal diagnosis of Pallister-Killian Syndrome (PKS) at 18 gestational weeks...

Caloric restriction (CR) is an intervention that can increase maximal lifespan in organisms, but its application to humans remains challenging. A more feasible approach to achieve lifespan extension is to develop CR mimetics that target biochemical pathways affected by CR. Recent studies in the engineering and structural characterization of polyketide synthases (PKSs) have facilitated their use as biocatalysts to produce novel polyketides. Here, we show that by establishing a combinatorial biosynthetic route in Escherichia coli and exploring the substrate promiscuity of a mutant PKS from alfalfa, 413 potential anti-ageing polyketides were biosynthesized...

Protein kinases (PKs) play a role in many pivotal aspects of cellular function. Dysregulation and mutations of protein kinases are involved in the development of different diseases, which might be treated by inhibition of the corresponding kinase. Protein kinase inhibitors (PKIs) are generally well tolerated, but unexpected and serious adverse events on the heart, lung, kidney and liver were observed clinically. In this study, the structure-activity relationship of PKIs in relation to hepatotoxicity was investigated...

Microalgal lipids have drawn great attention as a promising sustainable resource for biodiesel or food supplement production. The development of high-performance strains of microalgae by metabolic engineering is invaluable for increasing the quantity or quality of desired lipids. The synthesis routes of lipids used as biodiesel in microalgae are based on fatty acid synthase (FAS) and triacylglycerols (TAG) biosynthesis pathway. Polyunsaturated fatty acids (PUFAs), including ω-6 and ω-3 fatty acids, are essential nutrients for humans...